TY  - JOUR
AU  - Varbanov, Hristo
AU  - Jia, Shaobo
AU  - Kochlamazashvili, Gaga
AU  - Bhattacharya, Subhrajit
AU  - Buabeid, Manal Ali
AU  - El Tabbal, Mohamed
AU  - Hayani, Hussam
AU  - Stoyanov, Stoyan
AU  - Sun, Weilun
AU  - Thiesler, Hauke
AU  - Röckle, Iris
AU  - Hildebrandt, Herbert
AU  - Senkov, Oleg
AU  - Suppiramaniam, Vishnu
AU  - Gerardy-Schahn, Rita
AU  - Dityatev, Alexander
TI  - Rescue of synaptic and cognitive functions in polysialic acid-deficient mice and dementia models by short polysialic acid fragments.
JO  - Neurobiology of disease
VL  - 180
SN  - 0969-9961
CY  - [Amsterdam]
PB  - Elsevier
M1  - DZNE-2023-00470
SP  - 106079
PY  - 2023
AB  - Dysregulated cortical expression of the neural cell adhesion molecule (NCAM) and deficits of its associated polysialic acid (polySia) have been found in Alzheimer's disease and schizophrenia. However, the functional role of polySia in cortical synaptic plasticity remains poorly understood. Here, we show that acute enzymatic removal of polySia in medial prefrontal cortex (mPFC) slices leads to increased transmission mediated by the GluN1/GluN2B subtype of N-methyl-d-aspartate receptors (NMDARs), increased NMDAR-mediated extrasynaptic tonic currents, and impaired long-term potentiation (LTP). The latter could be fully rescued by pharmacological suppression of GluN1/GluN2B receptors, or by application of short soluble polySia fragments that inhibited opening of GluN1/GluN2B channels. These treatments and augmentation of synaptic NMDARs with the glycine transporter type 1 (GlyT1) inhibitor sarcosine also restored LTP in mice deficient in polysialyltransferase ST8SIA4. Furthermore, the impaired performance of polySia-deficient mice and two models of Alzheimer's disease in the mPFC-dependent cognitive tasks could be rescued by intranasal administration of polySia fragments. Our data demonstrate the essential role of polySia-NCAM in the balancing of signaling through synaptic/extrasynaptic NMDARs in mPFC and highlight the therapeutic potential of short polySia fragments to restrain GluN1/GluN2B-mediated signaling.
KW  - Mice
KW  - Animals
KW  - Alzheimer Disease: drug therapy
KW  - Sialic Acids: metabolism
KW  - Cognition
KW  - Neural Cell Adhesion Molecules: metabolism
KW  - Receptors, N-Methyl-D-Aspartate
KW  - NCAM (Other)
KW  - NMDA receptor (Other)
KW  - Polysialic acid (Other)
KW  - Prefrontal cortex (Other)
KW  - Synaptic plasticity (Other)
KW  - polysialic acid (NLM Chemicals)
KW  - Sialic Acids (NLM Chemicals)
KW  - Neural Cell Adhesion Molecules (NLM Chemicals)
KW  - Receptors, N-Methyl-D-Aspartate (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36918046
DO  - DOI:10.1016/j.nbd.2023.106079
UR  - https://pub.dzne.de/record/257594
ER  -